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Sublingual naloxone spray

a technology of naloxone and spray, applied in the direction of aerosol delivery, drug composition, inorganic non-active ingredients, etc., can solve the problems of patients not building up tolerance, naloxone does not appear to be addictive, and patients become addicted

Active Publication Date: 2017-05-09
HIKMA PHARMA USA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is directed to stable spray formulations containing naloxone, a drug used to treat opioid dependence and overdose. The formulations contain water, a cosolvent, and an antioxidant to prevent oxidation. They can be stored without alcohol and are safe for use in patients with opioid dependence or congenital insensitivity to pain with anhidrosis. The technical effect of the invention is the provision of a stable and safe spray formulation for the treatment of opioid dependence and overdose.

Problems solved by technology

One issue with other opioid dependence treatments is that they can become addictive.
Naloxone, however, does not appear to be addictive and patients do not build up a tolerance.
The quick metabolism may require repeat dosing or cause patient discomfort between doses.

Method used

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  • Sublingual naloxone spray

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Naloxone Formulations Containing Alcohol

[0088]Sublingual spray formulations were created by first degassing ethanol and USP purified water, separately. Next, the ethanol and purified water were each purged with nitrogen. Soluble excipients were then dissolved in either the ethanol or the purified water based on their solubility. Next, the solutions were combined. Naloxone was added to the final solution and mixed until dissolved.

[0089]Strawberry flavor was used as the source of the flavoring agent.

[0090]

TABLE 1Stable Sublingual Naloxone Spray FormulationsFormulationControl#1A#2A#3A#4A#5A#6A#7ANaloxone2.442.442.442.442.444.006.710.1Water (USP)37.5637.5537.5537.5437.5434.4533.2329.83Alcohol5555555555555555Propylene Glycol55555555L-menthol0.05Sodium Thiosulfate0.010.01Citric Acid0.0025Flavoring agent0.08Edetate disodium0.0050.0050.0050.0050.0050.005dihydrateBHA0.01BHT0.005Sodium Ascorbate0.020.020.020.02values = % w / w

example 2

Stability Testing of Naloxone Formulations

[0091]The formulations listed in Table 1 were subjected to stability testing at 40° C. and 55° C.±2° C. under 75%±5% relative humidity for eight weeks. The stability data was collected at zero, one, two, three, four, and eight weeks at 55° C. and at zero, four, and eight weeks at 40° C. Assay and impurities were detected using high performance liquid chromatography with an ultraviolet detector. The assay was performed at 288 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 240 nm and expressed as a % area. Amounts of particular impurities are listed in Tables 2A to 2F and 3A to 3H as a percentage of the area of each formulation along with amount of total impurities. “BQL” refers to “Below Quantifiable Limit” and “ND” refers to “Not Detected.”

Tables 2A to 2E. Stability Data for Sublingual Naloxone Spray Formulations Stored at 40° C.±2° C. Under 75%±5% Relative Humidity

[0092]

2A. Stability of Contr...

example 3

Droplet Testing

[0108]In order to determine the spray profile of Formulation #5A, it was subjected to standardized droplet testing. A challenge of creating a Naloxone sublingual spray formulation is that it must be capable of producing spray droplets that are over 10 microns in diameter. Spray droplets 10 microns or smaller could be inhaled into the lungs. The optimal particle size for sublingual spray droplets is from 20 to about 200 microns in diameter. It is desirable for the formulation to have droplet sizes near 20 because this increases the surface area and increased surface area exposure is one factor that contributes to a high bioavailability. Sublingual formulations should be able to maintain a consistent droplet size throughout its shelf life.

[0109]Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dv10, Dv50, Dv90, and Span were tested at two distances, 3 cm and 6 cm). Dv10 refers to drople...

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Abstract

The invention provides storage stable sublingual formulations containing naloxone, a pharmaceutically acceptable salt or a derivative thereof. The invention further provides methods for treating opioid dependence, opioid overdose, and congenital insensitivity to pain with anhidrosis by administering the sublingual formulations of the present invention to a patient in need thereof.

Description

FIELD OF THE INVENTION[0001]The invention is directed to sublingual spray formulations containing naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof. The invention is further directed to methods of treating opioid dependence, opioid overdose, and congenital insensitivity to pain with anhidrosis by administering sublingual spray formulations containing naloxone, pharmaceutically acceptable salts thereof, or derivatives thereof to a patient in need thereof.BACKGROUND OF THE INVENTION[0002]Naloxone has the following structure and is synthesized from thebaine:[0003][0004]Naloxone is most commonly used to treat patients suffering from opioid dependence or overdose because it is a competitive μ-opioid antagonist that blocks the effects of opioids. Naloxone is currently available in Suboxone® (Suboxone is a registered trademark of Reckitt Benckiser Healthcare (UK) Limited) as tablet or sublingual film strip formulations. Suboxone® contains buprenorphine and nalox...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/485A61K47/10A61K9/00
CPCA61K31/485A61K9/006A61K47/10A61K9/12A61K47/02A61K47/12A61K47/183A61P17/00A61P25/36
Inventor AMANCHA, KIRANCHILAMPALLI, SHIVANIPOTTA, THRIMOORTHYYAN, NINGXINGOSKONDA, VENKAT R.
Owner HIKMA PHARMA USA INC
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